Evidence continues to accumulate that immunological mechanisms are of central importance in atherogenesis, consistent with our current understanding of atherosclerosis as a chronic inflammatory disease. Our lab first demonstrated that epitopes of oxidized LDL (OxLDL) were immunodominant within the atherosclerotic plaque and that immunization of animals with a model of OxLDL, malondialdehyde modified LDL (MDA-LDL), was atheroprotective. We also demonstrated that immunization with a model oxidized phospholipid analogue found in OxLDL also provided atheroprotection. This suggests that an appropriate immunization strategy could be developed to inhibit atherogenesis. However, immunization with modified autologous LDL would not be practical for large populations. To develop a generalized vaccine requires the identification of the oxidation-specific epitope(s) that provides the atheroprotective immunity, but the actual chemical moieties generated by MDA modification of LDL are complex. The overall goal of these studies is to improve our understanding of immune responses to OxLDL and to initiate the development of a vaccine approach for the amelioration of atherosclerosis. To accomplish this we will identify specific immunogenic oxidation-specific epitope(s) that provide atheroprotective immunity, which could then be formulated into one or more vaccine approaches. We will synthesize a panel of MDA-lysine derived adducts, and a panel of oxidized phospholipid derived adducts, and use these to screen murine and human sera to determine the immunodominant chemical moieties. We will determine which of these candidate epitopes occur in vivo in atherosclerotic lesions and select candidates to test for their ability to be atheroprotective in cholesterol-fed LDL receptor deficient mice. We will develop a synthetic single epitope immunization strategy to test the immunogenicity and atheroprotective properties of selected epitopes in mice and we will determine mechanisms by which successful immunotherapy occurs. This information will improve our understanding of immune responses to OxLDL and could lead to the development of an immunization strategy that could be applied widely to ameliorate the progression of atherosclerosis. Lay Abstract: The immune system plays an important role in the development of atherosclerosis. We are trying to develop a vaccine that could be used to help prevent the progression of atherosclerosis